Asymmetric 1,4-functionalization of 1,3-enynes via dual photoredox and chromium catalysis

The merger of photoredox and transition-metal catalysis has evolved as a robust platform in organic synthesis over the past decade. The stereoselective 1,4-functionalization of 1,3-enynes, a prevalent synthon in synthetic chemistry, could afford valuable chiral allene derivatives. However, tremendous efforts have been focused on the ionic reaction pathway. The radical-involved asymmetric 1,4-functionalization of 1,3-enynes remains a prominent challenge. Herein, we describe the asymmetric three-component 1,4-dialkylation of 1,3-enynes via dual photoredox and chromium catalysis to provide chiral allenols. This method features readily available starting materials, broad substrate scope, good functional group compatibility, high regioselectivity, and simultaneous control of axial and central chiralities. Mechanistic studies suggest that this reaction proceeds through a radical-involved redox-neutral pathway.

Feng-Hua Zhang 1,2,3 , Xiaochong Guo 1,2,3 , Xianrong Zeng 1,2 & Zhaobin Wang 1,2 The merger of photoredox and transition-metal catalysis has evolved as a robust platform in organic synthesis over the past decade. The stereoselective 1,4-functionalization of 1,3-enynes, a prevalent synthon in synthetic chemistry, could afford valuable chiral allene derivatives. However, tremendous efforts have been focused on the ionic reaction pathway. The radical-involved asymmetric 1,4-functionalization of 1,3-enynes remains a prominent challenge. Herein, we describe the asymmetric three-component 1,4-dialkylation of 1,3enynes via dual photoredox and chromium catalysis to provide chiral allenols. This method features readily available starting materials, broad substrate scope, good functional group compatibility, high regioselectivity, and simultaneous control of axial and central chiralities. Mechanistic studies suggest that this reaction proceeds through a radical-involved redox-neutral pathway.
As our ongoing efforts in Cr-catalyzed radical-involved reactions 50 , we anticipate that the propargyl radical, which is in equilibrium with the allenyl radical, could be captured by a chiral chromium complex, and subsequent nucleophilic addition to the aldehyde affords the enantioenriched products (Fig. 1a, bottom). To achieve this goal, several challenges have to be addressed: (1) the regioselectivity control of 1,4-functionalization versus 1,2-functionalization; (2) the proper choice of radical precursors and photocatalysts to maintain the catalytic cycle; (3) the inhibition of quickly occurring side reactions from reactive radical intermediates or organochromium complexes.
Herein, we describe the three-component asymmetric radical 1,4functionalization of 1,3-enynes by merging photoredox and chromium catalysis (Fig. 1b). This reaction proceeds efficiently in a redox-neutral manner without an external reductant. And two C-C bonds are simultaneously constructed to provide chiral α-allenols with both a stereogenic center and a stereogenic axis, which serve as essential building blocks in total synthesis (Fig. 2) 51 . Furthermore, the application of versatile and readily accessible materials, including 1,3-enyne, aldehyde, radical precursors, endow the reaction with significant advantages in practical utility.

Reaction optimization
With the idea in mind, we initially explored the three-component reaction of benzaldehyde, 1,3-enyne 1, and DHP ester 2 (Table 1). After detailed investigations of a series of reaction parameters, we determined that the merger of a chiral chromium/cyano-bisoxazoline ((S,R)-L1) and a photocatalyst 4-CzIPN could achieve the chemoselective allenylation reaction in good yield and high diastereoselectivity and enantioselectivity under visible-light irradiation (entry 1). Control experiments establish that CrCl 2 , 4-CzIPN, and light are critical for this allenylation reaction under these conditions (entries 2-4). A slight decrease in enantioselectivity was detected when using a similar anionic ligand L2 (entry 5). Other chiral nitrogen-containing ligands are not effective for this reaction under similar conditions (entries 6-10). In the case of L6, the homopropargylic alcohol was isolated in 1:3 ratio vs the allenol (entry 9). The reaction also performed well in DME, CH 3 CN, or EtOAc, furnishing the desired chiral allenol only with a slight decrease in yield and dr (entries [11][12][13]. The photocatalyst [Ir(dF(CF 3 )ppy) 2 (dtbpy)]PF 6 also led to the allenol but with a slight erosion in d.r. and ee (entry 14). Decreasing the catalyst loading to 5 mol% CrCl 2 and 6 mol% (S,R)-L1 led to a drop in yield (entry 15). When increasing the concentration from 0.05 M to 0.1 M, the d.r. decreased from 20:1 to 12:1 (entry 16). And the yield or dr of the allenylation product was only modestly diminished, if 1.2 equivalent of 1,3-enyne 1 and DHP ester 2 are used (entries 17&18). However, adding 1.0 equivalent water to the reaction mixture inhibits the formation of α-allenol 3 (entry 19). The addition of 1.0 mL air to the reaction vessel has a deleterious effect (entry 20). These results indicated that the reaction was sensitive to moisture and air, probably due to the involvement of unstable alkyl chromium complexes.
Naturally occurring α-amino acids are readily available and act as prevalent feedstocks in asymmetric synthesis 56 . We were delighted to find that the chiral α-amino aldehydes, derived from natural amino acids, served as effective substrates under the standard condition for synthesizing chiral amino alcohols with continuous two stereogenic centers and one chiral axis (Fig. 3, 40-49). As indicated by the singlecrystal structure for products 12 and 42 (see Supplementary Information), the chiral chromium catalyst, rather than existing stereocentres on the chiral aldehydes, predominantly determines the stereochemistry of the allenylation products 40-49. It is noteworthy that chiral amino alcohols are prevalent synthons in pharmaceuticals and asymmetric catalysis 57 . Finally, the reactivity of α,β-unsaturated aldehydes was tested, and the desired chiral α-allenols were obtained in high yields and diastereoselectivities after increasing the equivalents of 1,3-enyne 1 and DHP ester 2 (Fig. 3, 50 and 51).
Organotrifluoroborates, featuring tetracoordinate boron with strong boron-fluoride bonds, are generally stable toward numerous regents that are often problematic for other trivalent organoborons, and thus have been widely used in Suzuki-Miyaura couplings 58 . Moreover, organotrifluoroborates also prove to be suitable radical precursors for C-C bond construction via photoredox catalysis 59,60 . In this context, we applied them as radical precursors to our newly developed method. After further evaluation of different reaction parameters, we determined an optimal condition with the acridine tetrafluoroborate (PC-2) as the photocatalyst and 2,6-dimethylpyridine hydrochloride as the dissociation reagent. Thus, the representative secondary organotrifluoroborates engaged well in the 1,4-functionalization of enynes with aryl and aliphatic aldehydes to efficiently afford the desired coupling products (Fig. 5a, 53, 56, 71, and 72). N-(Acyloxy)phthalimides (NHPI esters) are widely available from carboxylic acids, and have proved to be priviliged alkyl radical precursors in decarboxylitive cross-couplings 61,62 . Gratifyingly, NHPI esters also work well under a slightly modified condition with Hantzsch ester as the reductant, furnishing the desired allenols in moderate to good yield and high stereoselectivity (Fig. 5b, 1, 31, 53, and 58).

Synthetic application
Product transformations were performed to demonstrate the synthetic utility of our newly developed method (Fig. 5c). Chiral α-allenols serve as suitable building blocks in the synthesis of enantioenriched dihydrofurans 63 . The desilylation reaction of 63 proceeded smoothly, affording the chiral α-allenol 73 without losing diastereomeric or enantiomeric excess. The stereoselective electrophilic cyclization of 73 furnished 2,5-dihydrofurans 74 and 75 with good efficiency in axialto-central chirality transfer (Fig. 5c).

Mechanistic observations
A series of conventional experiments were conducted to provide insights into the reaction mechanism (Fig. 6a-c). The addition of 2 equiv of an allyl sulfone under the standard condition led to an adduct 76 in 42% yield, with a trace amount of desired product 3, which suggested that the reaction might involve the formation of cyclohexyl radical from the DHP ester (Fig. 6a). According to a reported method 64 , the quantum yield of this model reaction was determined to be 0.35. Moreover, the direct correlation between photolysis and product formation is demonstrated by an interval light-dark reaction (Fig. 6b). These results indicate that the radical 1,4-functionalization process undergoes a photoredox, instead of a radical-chain, pathway. As shown in Fig. 6c, the Stern-Volmer luminescence quenching studies proved that the DHP ester, rather than the 1,3-enyne, quenches the excited-state photocatalyst 4-CzIPN, suggesting a reductive quenching pathway.     According to our observations and previous reports 44,46,47 , a putative mechanism is proposed in Fig. 6d with the model reaction as an example. The excited-state photocatalyst PC* 4-CzIPN* (E 1/2 (*PC/ PC˙ˉ) = 1.35 V vs. SCE in MeCN) 65 is reductively quenched by the DHP ester 2 (E 1/2 = 1.10 V vs. SCE in MeCN) 66 , generating the reduced photocatalyst PC˙ˉand the radical cation A. The rapid fragmentation of intermediate A affords the isopropyl radical and the pyridinium B. The isopropyl radical could either reversibly add to the low valent Cr II /L1 to 10    generate an off-cycle alkyl Cr III /L1 complex 67 , or add to the terminus of 1,3-enyne 1 to forge the propargyl radical C, which is in equilibrium with the allenyl radical C'. The radical capture by Cr II /L1 leads to two equilibrated species, the propargyl chromium D and allenyl chromium D'. Subsequent nucleophilic attack to benzaldehyde is proposed via a six-member cyclic manner 68 , affording intermediate E. We believe that the isomerization between intermediates D and D' is faster than the subsequent nucleophilic addition to aldehydes. So the regioselectivity might be determined in the nucleophilic carbonyl addition step via a possible Zimmerman-Traxler transition state. As observed in the scope study, the steric hindrance of the acetylenic substituents of 1,3-enynes is critical for the high regioselectivity, which favors the allenylation product formation from the propargyl Cr D, instead of the allenyl D'. The dissociation of the O-Cr bond in E by the pyridinium B, provides chiral allenol 3. Finally, the Cr III /L1 is reduced to Cr II /L1 (E 1/2 = -0.65 V vs. SCE in H 2 O, E 1/2 = -0.51 V vs. SCE in DMF) 47 by the reduced photocatalyst PC˙ˉ(E 1/2 (PC/PC˙ˉ) = -1.21 V vs. SCE in MeCN) 65 , which closes the catalytic cycle.
In conclusion, we described a three-component asymmetric radical 1,4-functionalization of 1,3-enynes via dual photoredox and chromium catalysis. The key to success is using DHP esters under photoredox conditions, thus obviating stoichiometric amounts of metal reductants and dissociation reagents in conventional catalytic NHK reactions. The present method exhibits broad substrate scope with good functional group compatibility, providing efficient access to valuable chiral α-allenols from the readily available starting material. Given the importance of allenols and the growing interest in metallaphotoredox catalysis 37 , we anticipate that our protocol will find broad utility in organic synthesis and facilitate the current endeavors to develop dual catalytic systems.

Methods
General procedure for radical 1,4-functionalization of 1,3-enynes with aldehydes and DHP esters In a nitrogen-filled glovebox, an oven-dried 20 mL vial with a magnetic stir bar, were charged with the CrCl 2 (5.0 mg, 0.04 mmol, 10 mol%) and (S,R)-L1 (23.2 mg, 0.048 mmol, 12 mol %). Then 8.0 mL THF was added via syringe. The vial was closed with a PTFE septum cap and then stirred at room temperature for 2 hours. Next, to the prepared catalyst solution were added the 1,3-enynes (0.6 mmol, 1.5 equiv), the aldehydes (0.4 mmol, 1.0 equiv), the DHP esters (0.6 mmol, 1.5 equiv), and photocatalyst 4-CzIPN (6.4 mg, 0.008 mmol, 2 mol%) sequentially. Then the vial was closed with a PTFE septum cap and taken out of the glovebox. The reaction was irradiated with two 20 W 160-440 nm LED for 12 h (tube 5 cm away from lights, fans for cooling, 30-35°C). After that, the reaction mixture was concentrated and run through a short silica gel pad with hexanes/EtOAc (3:1) as the eluent. Then the solvent was removed under the reduced pressure. The diastereoselectivity was determined via 1 H NMR analysis of the crude reaction mixture. The residue was purified by flash chromatography to provide the desired product, and the ee was determined via HPLC/SFC analysis.

Data availability
The data relating to the materials and methods, experimental procedures, HPLC/SFC spectra, mechanism research, and NMR spectra are available in the Supplementary Information. The crystallographic data for compounds 12 and 42 are available free of charge from the CCDC under reference numbers 2130059 and 2130062. All other data are available from the authors upon request.